Ubiquitylation in apoptosis: a post-translational modification at the edge of life and death

The proper regulation of apoptosis is essential for the survival of multicellular organisms. Furthermore, excessive apoptosis can contribute to neurodegenerative diseases, anaemia and graft rejection, and diminished apoptosis can lead to autoimmune diseases and cancer. It has become clear that the post-translational modification of apoptotic proteins by ubiquitylation regulates key components in cell death signalling cascades. For example, ubiquitin E3 ligases, such as MDM2 (which ubiquitylates p53) and inhibitor of apoptosis (IAP) proteins, and deubiquitinases, such as A20 and ubiquitin-specific protease 9X (USP9X) (which regulate the ubiquitylation and degradation of receptor-interacting protein 1 (RIP1) and myeloid leukaemia cell differentiation 1 (MCL1), respectively), have important roles in apoptosis. Therapeutic agents that target apoptotic regulatory proteins, including those that are part of the ubiquitin-proteasome system, might afford clinical benefits.     

T-cell signalling and immune system disorders

T-cell receptor (TCR) engagement initiates intracellular signalling cascades that lead to T-cell proliferation, cytokine production and differentiation into effector cells. These cascades comprise an array of protein-tyrosine kinases, phosphatases, GTP-binding proteins and adaptor proteins that regulate generic and specialised functions. The integration of these signals is essential for the normal development, homeostasis and function of T cells. Defects in a single mediator can produce T cells that are unable to participate fully in an immune response and/or that mount an inappropriate response, which leads to immunodeficiency, autoimmunity or leukaemia/lymphomas. This review highlights some of the key players in T-cell signalling and their involvement in the development of various clinical disease states. Some of these immune-specific signalling proteins are attractive potential targets in the development of therapies to augment T-cell responses to antigen or tumours, and to treat immune cell disorders.     

植物信号传导中的磷脂酶

20世纪 80年代早期人们意识到构成细胞膜的磷脂不只是一道将细胞物质与外界隔开的屏障,而且是细胞对外界环境刺激作出应答的物质基础。磷脂酰肌醇（ｐｈｏｓｐｈｏｔｉｄｙｌｉｎｏｓｉｔｏｌ,ＰＩ）不但是构成细胞膜的重要组分（约占细胞膜组分的 10 %）,在细胞内外环境信号的传递方面也起着重要的作用［1］。磷脂酶（ｐｈｏｓｐｈｏｌｉｐａｓｅ）水解磷脂后产生的三磷酸肌醇 （ｉｎｏｓ ｉｔｏｌｔｒｉｓｐｈｏｓｐｈａｔｅ,ＩＰ3 ）／二酰基甘油（ｄｉａｃｙｌｇｌｙｃｅｒｏｌ,ＤＡＧ）、磷脂酸（ｐｈｏｓｐｈａｔｉｄｉｃａｃｉ…     

SLP76 and SLP65: complex regulation of signalling in lymphocytes and beyond

SLP76 and SLP65 are adaptor proteins that lack intrinsic enzymatic activity but contain multiple protein-binding domains. These proteins are essential for signalling downstream of integrins and receptors that contain immunoreceptor tyrosine-based activation motifs. The absence of these adaptor proteins profoundly affects various lineages in the haematopoietic compartment and severely compromises vascular development, highlighting their importance as regulators of signalling cascades. In this Review, we discuss the role of SLP76 and SLP65 in several signalling pathways in haematopoietic cells, with an emphasis on recent studies that provide insight into their mechanisms of action.     

Glycosylation regulates Notch signalling

Intracellular post-translational modifications such as phosphorylation and ubiquitylation have been well studied for their roles in regulating diverse signalling pathways, but we are only just beginning to understand how differential glycosylation is used to regulate intercellular signalling. Recent studies make clear that extracellular post-translational modifications, in the form of glycosylation, are essential for the Notch signalling pathway, and that differences in the extent of glycosylation are a significant mechanism by which this pathway is regulated.     

Heterotrimeric G-proteins mediated hormonal responses in plants

Phytohormones not only orchestrate intrinsic developmental programs from germination to senescence but also regulate environmental inputs through complex signalling pathways. Despite building an own signalling network, hormones mutually contribute several signalling systems, which are also essential for plant growth and development, defense, and responses to abiotic stresses. One of such important signalling cascades is G-proteins, which act as critical regulators of a wide range of fundamental cellular processes by transducing receptor signals to the intracellular environment. G proteins are composed of α, β, and γ subunits, and the molecular switching between active and inactive conformation of Gα controls the signalling cycle. The active GTP bound Gα and freed Gβγ have both independent and tightly coordinated roles in the regulation of effector molecules, thereby modulating multiple responses, including hormonal responses. Therefore, an interplay of hormones with G-proteins fine-tunes multiple biological processes of plants; however, their molecular mechanisms are largely unknown. Functional characterization of hormone biosynthesis, perception, and signalling components, as well as identification of few effector molecules of G-proteins and their interaction networks, reduces the complexity of the hormonal signalling networks related to G-proteins. In this review, we highlight a valuable insight into the mechanisms of how the G-protein signalling cascades connect with hormonal responses to regulate increased developmental flexibility as well as remarkable plasticity of plants.     

Auxin regulation of cell cycle and its role during lateral root initiation

The plant hormone auxin plays a crucial role in the upstream regulation of many processes, making the study of its action particularly interesting to understand plant development. In this review we will focus on the effects auxin exerts on cell cycle progression, more specifically, during the initiation of lateral roots. Auxin fulfils a dominant role in the initiation of a new lateral root primordium. How this occurs remains largely unknown. Here we try to integrate the classical auxin signalling mechanisms into recent findings on cell cycle regulation. How both signalling cascades are integrated appears to be complex and is far from understood. As a means to solve this problem we suggest the use of a lateral root-inducible system that allows investigation of the early signalling cascades initiated by auxin and leading to cell cycle activation.     

Two mitogen-activated protein kinase signalling cascades mediate basal resistance to antifungal plant defensins in Fusarium graminearum

Antifungal defensins, MsDef1 and MtDef4, from Medicago spp., inhibit the growth of Fusarium graminearum, which causes head blight disease in cereals. In order to determine the signalling cascades that are modulated by these defensins, we have isolated several insertional mutants of F. graminearum that exhibit hypersensitivity to MsDef1, but not to MtDef4. The molecular characterization of two of these mutants, designated enhanced sensitivity to defensin (esd), has revealed that the Mgv1 and Gpmk1 MAP kinase signalling cascades play a major role in regulating sensitivity of F. graminearum to MsDef1, but not to MtDef4. The Hog1 MAP kinase signalling cascade, which is responsible for adaptation of this fungus to hyperosmotic stress, does not participate in the fungal response to these defensins. Significantly, the esd mutants also exhibit hypersensitivity to other tested defensins and are highly compromised in their pathogenesis on wheat heads and tomato fruits. The studies reported here for the first time implicate two MAP kinase signalling cascades in a plant defensin-mediated alteration of fungal growth. Based on our findings, we propose that specific MAP kinase signalling cascades are essential for protection of a fungal pathogen from the antimicrobial proteins of its host plant.     

Bacteria and the ubiquitin pathway

Ubiquitylation participates in a repertoire of reversible post-translational modifications that modulate the function, localization and half-life of proteins by regulating their association with various ubiquitin-binding proteins. In response to pathogen infection, bacterial effectors impact ubiquitin and ubiquitin-like modifications of key proteins in immune and anti-apoptotic signaling cascades. Certain bacteria corrupt the ubiquitylation machinery in order to regulate their virulence factors spatially and temporally or to trigger internalization of bacteria into host cells. Several new examples of how bacterial factors target ubiquitin and ubiquitin-like regulation emphasize the importance of modulating ubiquitin signaling to establish either long-lasting or devastating relationships of bacteria with their hosts.     

Caspases at the crossroads of immune-cell life and death

Caspases are responsible for crucial aspects of inflammation and immune-cell death that are disrupted in a number of genetic autoimmune and autoinflammatory diseases. The caspase family of proteases can be divided into pro-apoptotic and pro-inflammatory members based on their substrate specificity and participation in separate signalling cascades. However, as discussed here, evidence has emerged over the past few years that a number of the caspases thought to be involved solely in apoptosis also contribute to specific aspects of immune-cell development, activation and differentiation, and can even protect cells from some forms of cell death.     

Ubiquitin links to cytoskeletal dynamics, cell adhesion and migration

Post-translational modifications are used by cells to link additional information to proteins. Most modifications are subtle and concern small moieties such as a phosphate group or a lipid. In contrast, protein ubiquitylation entails the covalent attachment of a full-length protein such as ubiquitin. The protein ubiquitylation machinery is remarkably complex, comprising more than 15 Ubls (ubiquitin-like proteins) and several hundreds of ubiquitin-conjugating enzymes. Ubiquitin is best known for its role as a tag that induces protein destruction either by the proteasome or through targeting to lysosomes. However, addition of one or more Ubls also affects vesicular traffic, protein-protein interactions and signal transduction. It is by now well established that ubiquitylation is a component of most, if not all, cellular signalling pathways. Owing to its abundance in controlling cellular functions, ubiquitylation is also of key relevance to human pathologies, including cancer and inflammation. In the present review, we focus on its role in the control of cell adhesion, polarity and directional migration. It will become clear that protein modification by Ubls occurs at every level from the receptors at the plasma membrane down to cytoskeletal components such as actin, with differential consequences for the pathway's final output. Since ubiquitylation is fast as well as reversible, it represents a bona fide signalling event, which is used to fine-tune a cell's responses to receptor agonists.     

RNF146 is a poly(ADP-ribose)-directed E3 ligase that regulates axin degradation and Wnt signalling

The Wnt/β-catenin signalling pathway plays essential roles in embryonic development and adult tissue homeostasis, and deregulation of this pathway has been linked to cancer. Axin is a concentration-limiting component of the β-catenin destruction complex, and its stability is regulated by tankyrase. However, the molecular mechanism by which tankyrase-dependent poly(ADP-ribosyl)ation (PARsylation) is coupled to ubiquitylation and degradation of axin remains undefined. Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation. Thus, identification of RNF146 as a PARsylation-directed E3 ligase establishes a molecular paradigm that links tankyrase-dependent PARsylation to ubiquitylation. RNF146-dependent protein degradation may emerge as a major mechanism by which tankyrase exerts its function.     

p38 MAPK signalling cascades: ancient roles and new functions

p38 MAPKs are a conserved subfamily of MAPKs involved in the response to stress found in eukaryotic cells from yeast to mammals. The recent isolation of genes coding for members of this signalling cascade in Drosophila has provided us with the genetic tools to study their various biological roles and their regulatory interactions with other signalling pathways. This cascade participates in the immune response, a function that is remarkably conserved between flies and humans. Additionally, it appears to exert other fundamental roles during development, in cell fate specification in imaginal discs, and in cell polarity during oogenesis. These functions involve genetic and biochemical interactions with other signalling cascades, the decapentaplegic/TGFbeta, the wingless/Wnt and the torpedo/Ras-ERK pathways. In the near future, we can expect a flurry of information that will allow us to draw a comprehensive picture of the roles of signalling networks mediated by p38s during development.     

Lipid rafts and B-cell activation

The B-cell antigen receptor acts during B-cell activation both to initiate signalling cascades and to transport antigen into the cell for subsequent processing and presentation. Recent evidence indicates that membrane microdomains, termed lipid rafts, have a role in B-cell activation as platforms for B-cell receptor (BCR) signalling and might also act in antigen trafficking. Lipid rafts might facilitate the regulation of the BCR during B-cell development by B-cell co-receptors, and during viral infection. So, lipid rafts seem to be an important new piece of the B-cell signalling puzzle.